Vascular endothelial growth factor (VEGF)-C has been shown to be necessary for lymphangiogenesis and may be useful for lymphangiogenic therapy in diseases of inadequate lymphatic drainage. Although a number of recent studies have reported that overexpression of VEGF-C can promote lymphangiogenesis and improve lymphatic function, we have found that the ability of excess lymphatic growth factor alone to increase functional lymphatic growth above physiological levels may be limited. We have also found that experimental lymphedema is able to resolve in the absence of lymphangiogenesis. Clinically, compressive garments have been shown to produce significant reductions in the swelling of the edematous human arm. These results suggest that interstitial flow (IF) dynamics across the obstruction site may be important for resolution of lymphedema and that IF can be increased in the edematous arm without prior stimulation of lymphatic growth. Therefore therapies that directly increase IF may be beneficial for lymphedema. It has recently been demonstrated that fluid channels are formed by IF and that endogenous VEGF-C promotes lymphatic endothelial cell (LEC) migration along the fluid channel scaffold during early stages of lymphangiogenesis. We hypothesize that compressive loading may increase IF by increasing fluid channel formation and that combining VEGF-C therapy with compressive loading may improve functional lymphangiogenesis by convecting VEGF-C through fluid channels and establishing VEGF-C gradients that can direct functional lymphatic growth. We aim to determine whether compressive loading may increase IF by increasing the formation of fluid channels, whether an augmentation of fluid channels by compression in conjunction with exogenous VEGF-C protein may enhance functional lymphangiogenesis and improve lymphedema, and whether cyclic compressive loading may increase IF relative to static compressive loading. PUBLIC HEALTH RELEVANCE: Lymphedema often follows axillary lymph node dissection from breast cancer surgery. Although compression therapy reduces lymphedema, the mechanism of action is not clear. We aim to clarify the role of compression in regulating interstitial flow and to determine the ability of combined compression/lymphangiogenesis therapy to improve lymphedema.